Neuropathic pain states are characterized by both negative symptoms (sensory loss, numbness) and the positive symptoms of allodynia, hyperalgesia and ongoing pain that are unlike the consequences of damage to our other sensory systems. These positive symptoms strongly suggest changes within the nervous system that are excessive attempts to compensate for sensory loss. The initial events of neuropathic pain are thought to be generated in the peripheral sensory neurones within the nerve itself at the site of damage and so are independent of peripheral nociceptor activation. Following damage to peripheral nerves, a number of changes can be produced, in terms of activity, properties and transmitter content. Damaged nerves may start to generate ongoing "ectopic" activity where patterns of excitability and conduction in primary afferent fibers (PAF) are markedly altered. Nerve endings may also seal off and sometimes unsuccessfully attempt to sprout, resulting in the formation of a neuroma which can often lead to abnormal mechanosensitivity .
The causes of the spontaneous ectopic activity are thought to involve sodium channel receptor accumulation and clustering in the PAF neuroma , but may also involve changes of the density or functional properties of calcium and potassium channels [22-25]. These changes may also be dependent on the type of nerve damage encountered since the expression of tetrodotoxin (TTX)-resistant sodium channels, for example, is downregulated following axonal lesions but upregulated following inflammation . This aberrant activity can then start to spread rapidly to the cell body in the dorsal root ganglia (DRG). In addition to changes within the nerve, sympathetic efferents become able to activate sensory afferents. These peripheral ectopic impulses can cause spontaneous pain and hyperalgesia. This peripheral activity may be a rational basis for the use of systemic local anesthetics, such as lignocaine, in neuropathic states since damaged nerves have been shown to be highly sensitive to systemic sodium channel blockers
[27-29]. This too is probably part of the basis for the mechanisms of established effective anticonvulsants that block sodium channels, such as carbamazepine  and phenytoin .
The potential for a systemic drug that blocks pain-related sodium channels has now gained impetus as at least two sodium channels with either unique (Nav 1.8) or selective (Nav 1.7) localization in small afferents have been validated [32, 33]. The former has a selective blocker, effective in preclinical models , and the latter has been shown to be implicated in human familial pain disorders [35, 36]. If effective in humans, these agents could provide truly novel approaches to pain control.
Gabapentin and pregabalin are drugs licensed for neuropathic pain that have analgesic activity in neuropathic pain states from varying origins. In randomized controlled trials both gabapentin and pregabalin have demonstrated their value in the treatment of pain associated with diabetic peripheral neuropathy and postherpetic neuralgia [37-39]. The mechanism of action of gabapentin and pre-gabalin is now clearly established; although both drugs are lipophilic analogs of GABA, their analgesic action is attributed to their interaction with the auxiliary-associated protein a2S subunit, common to all voltage-gated calcium channels [40, 41]. In animals, gabapentin displays state-dependent analgesia inasmuch as it selectively inhibits altered neuronal function resulting from neuropathy whilst leaving normal activity unaffected [41- 44]. This ability to alter abnormal activity in a somewhat selective manner may partly result from the fact that the spinal cord a2S subunit is upregulated after nerve injury accompanied by functional changes in the roles of a number of calcium channels .
However, this is not the only factor that governs this state dependency, with pathways from midbrain hyperalgesic systems also participating. A likely pathway involves spinal lamina I substance P-respon-sive neurones which project to the parabrachial region and subsequently the rostroventral medulla (RVM) where descending serotonergic pathways can become activated, modulating spinal excitability through spinal neurones with substance P-saporin (SP-SAP), or intrathecal administration of the 5HT antagonist ondansetron, attenuates mechanical and tactile hypersensitivity and aberrant neuronal coding following spinal nerve injury. Furthermore, in these animals, gabapentin efficacy can be switched on and off by interference with these 5HT-3 systems .
This descending facilitatory serotonergic drive is thought to play only a minor role under normal conditions compared with pathophysiological conditions  and may be important not only in neuropathy but also in dysfunctional pains where not only is 5HT implicated but these pathways provide a route by which abnormal central processing can diffusely increase spinal sensitivity. Human imaging studies have verified these circuits in non-neuropathic pains and shown an interaction with gabapentin [47, 48].
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